Control of Outflow Resistance by Soluble Adenylyl Cyclase

Abstract

Glaucoma is a leading cause of blindness in the United States affecting as many as 2.2 million Americans. All current glaucoma treatment strategies aim to reduce intraocular pressure, even in patients with normal tension glaucoma. Typically, this is accomplished by reducing the rate of aqueous flow by limiting aqueous production or enhancing drainage using drugs and surgery. Whereas these strategies are effective in diminishing vision loss, some patients continue to lose vision and many discontinue use of their medications because of undesirable side effects. Drugs known to be effective in altering conventional outflow have for the most part been abandoned from modern clinical practice due to undesirable side effects. Identification of new drugs that could enhance conventional outflow, would offer additional options in the treatment of glaucoma and ocular hypertension. To this end, our laboratory has recently uncovered a novel pathway for regulation of conventional outflow by the ciliary body. This pathway is dependent on soluble adenylyl cyclase, an enzyme that catalyzes the generation of cyclic adenosine 3¢,5¢ monophosphate (cAMP) in response to bicarbonate.

Role of cyclic AMP in the eye with glaucoma

“…examined the influence of carbonic anhydrase inhibitors on sAC and found that acetazolamide increases the sAC-generated cAMP level in the ciliary epithelium, suggesting the possibility that sAC-mediated increasing of the cAMP level can lower IOP ( 67 ). Previous studies revealed that sAC contributes to the regulation of conventional outflow ( 68 ). In these studies, Bestropin 2 (Best2), an anion channel, was characterized as a bicarbonate channel ( 69 ), and Best2 was present only in the non-pigmented epithelium of the ciliary body in the eye ( 68 , 70 ).…”

“…Previous studies revealed that sAC contributes to the regulation of conventional outflow ( 68 ). In these studies, Bestropin 2 (Best2), an anion channel, was characterized as a bicarbonate channel ( 69 ), and Best2 was present only in the non-pigmented epithelium of the ciliary body in the eye ( 68 , 70 ). Furthermore, Best2 knockout mice show a significant IOP lowering compared with wild-type (WT) control littermates ( 71 , 72 ).…”

“…Collectively, these studies suggest that sAC is critical for regulating IOP. Because no sAC expression is observed in drainage-associated tissues, such as the TM/SC complex of the mouse ( 65 ), it is proposed that there may be an unknown biochemical pathway for communication between the ciliary body and drainage tissues, one that is regulated by HCO 3 − and cAMP ( 65 , 68 ). However, the precise mechanism of the IOP regulation by sAC remains unknown.…”

Differential Intraocular Pressure Measurements by Tonometry and Direct Cannulation After Treatment with Soluble Adenylyl Cyclase Inhibitors

“…KH7 and LRE1, specific inhibitors of soluble adenylyl cyclase (sAC), have been proposed as therapeutic agents for ocular hypotony. [9][10][11] sAC is found in the ciliary body and is known to catalyze the formation of cAMP in response to increasing intracellular bicarbonate [HCO 3 -]. 12,13 KH7 has previously been shown to increase IOP in mice through direct cannulation.…”

Regulation of Aqueous Humor Dynamics by Hydrogen Sulfide: Potential Role in Glaucoma Pharmacotherapy

“…Interestingly, the observation that increases in AH outflow facility induced by NaHS and l-cysteine can be blocked by an inhibitor of adenylyl cyclase is noteworthy based on the fact that this nucleotide has been implicated in the overall regulation of AH dynamics. 67 The perfused ocular anterior segment model preserves the architecture of the outflow pathway and has been used extensively in ex vivo studies of the pharmacological actions of drugs on AH dynamics. [68][69][70] Clearly, the increase in outflow facility induced by H 2 S-releasing compounds suggests that an effect on conventional outflow channels could underlie, at least in part, a mechanism of IOP-lowering action of this gas in mammals.…”